Neuroscientists at the University of California, San Francisco, had a hunch their findings would be controversial, as tends to happen when you challenge popular, world-changing brain research. They were right.
Their study, published in Nature on Wednesday, concludes that the adult human brain does not produce any detectable new neurons in the area that’s supposedly ground zero for neuronal creation, contrary to dozens of experiments over the last 20 years. The idea that the brain is capable of “neurogenesis” well into old age has inspired hope that the process might be harnessed to treat memory loss, cognitive decline, depression, and more. But based on an examination of more than 50 brains, the UCSF team said neuron formation ends by late childhood.
“In adult brains, we couldn’t find a single new neuron,” said co-lead author Shawn Sorrells.
The pushback against the new study was immediate.
“They may just not have looked carefully enough,” said Jonas Frisén, of Sweden’s Karolinska Institute, who in 2015 discovered a novel way of detecting adult neurogenesis.
With the new study’s methods, “it would not have been possible to prove adult neurogenesis,” said Gerd Kempermann of the German Center for Neurodegenerative Diseases in Dresden, who has studied the phenomenon for decades. Because the molecular markers of neurogenesis that the UCSF scientists used are imperfect, he said, failing to find those proxies “cannot qualify as sufficient proof of the non-existence of adult human [neurogenesis],” so their claim is “off-target.”
The findings “are in stark contrast to the prevailing view” and “certain to stir up controversy,” neuroscientist Jason Snyder of the University of British Columbia wrote in a commentary on the study for Nature.
If the UCSF researchers are right, 20 years of neuroscience textbooks have to be rewritten, explanations for how physical activity helps cognition may have to be scrapped, and hopes that neurogenesis might be enlisted to treat brain disorders are probably pipe dreams. Understanding of the human brain would return to what it was in the late 1990s, before scientists at the Gothenburg Research Institute and the Salk Institute for Biological Studies reported that the brain can generate new neurons, which carry brain signals, well into middle age and even later. There had been glimpses of that in the 1960s, but the 1998 study launched the field of human neurogenesis, which has been going strong ever since.
The claim has long been shadowed by questions, however. It’s not possible to watch a living human brain generate new neurons in real time. Scientists therefore study the next best thing: brains of the recently deceased. But although those brains can be sliced and diced, it isn’t possible to directly see neurogenesis. “You can’t just shine light onto a skull and see it,” said Salk Institute neurobiologist Fred Gage, who led the 1998 study.
Instead, scientists have to use proxies. The “gold standard” for detecting neurogenesis is to give living people a molecule that becomes incorporated into the DNA of dividing cells and therefore marking the new neurons that the dividing cells produce, said Gage. The incorporated molecules, which can be detected after a volunteer dies, act as time stamps, revealing if and when new neurons were born. Even if the person dies many years after being given the molecule, Gage said, “you can still detect if neurogenesis took place.”
The new study, led by UCSF’s Arturo Alvarez-Buylla and including researchers from Spain and China, also used proxies. They made ultra-thin slices of tissue samples from 59 brains of people who died across the age span — fetuses, children, teenagers, and adults up to age 77, healthy or with epilepsy — and looked for molecules thought to indicate the presence of new neurons. They found robust neurogenesis before birth; no surprise, since that’s when the brain is forming. They also found it in early childhood. They did not find it in brains older than 13.
Neurogenesis, they wrote, “declines sharply during the first year of life”: At birth, there is an average of 1,600 new neurons in an area of brain 1 millimeter across, but by age 1 that falls to about 300. By age 7, brains have only a few new neurons, they found.
The conclusion that the birth of new neurons declines with age jibes with dozens of studies reporting an age-related drop-off. But the claim that adult brains create zero new neurons is so at odds with other studies that neuroscientists across the world were writing sharp critiques even before Nature published the new paper.
The concerns center on the difficulty of interpreting the molecular markers that are supposed to signal neurogenesis, especially in adult brains that have been dead for more than a few hours.
The UCSF team used multiple markers, with names like doublecortin, DCX, and PSA NCAM, believed to indicate the presence of cells that give rise to new neurons. But they did not look for these markers in living brains. The problem with not giving the molecular markers while the brain is alive is that the ability to detect them “disappears within a few hours of death,” Gage said. Because many of the brains were analyzed after a longer wait, “it’s not surprising you can’t see neurogenesis.”
Kempermann said one marker the UCSF team used “is very difficult,” especially in non-living brains, because it degrades very quickly and therefore can vanish even if neurogenesis was present. In a 2010 study of 54 brains aged from birth to 100, he and his colleagues used some of the same markers as the UCSF scientists, plus additional ones, and found “a pattern of adult neurogenesis,” he said. “We came to exactly the opposite conclusion. There is no validation in the [new] paper that the absence of the marker really means the absence of the phenomenon.”
The UCSF scientists defended their method. One check on its reliability was that the markers of neuron-making cells were present in the brains of fetuses and young children, said co-lead author Mercedes Paredes. And microscopic examination of the very young brains showed “classic signs of new neurons,” said Sorrells: “cells with elongated nuclei and no dendrites or axons.”
Critics countered that the neurogenesis markers work better on young brains. They also said that requiring the presence of multiple markers was too strict.
Alvarez-Buylla said he and his colleagues looked for neurogenesis only in the hippocampus, the brain’s memory-forming structure, and are not ruling it out for other regions. But years of research have looked for neurogenesis elsewhere and basically come up empty; it’s the hippocampus or nothing. As for why dozens of studies have found neurogenesis, Paredes said, it might be because the same molecules used to infer the birth of neurons can also mark ordinary cell processes such as DNA repair. “It’s still up in the air what these [markers] are labeling,” she said.
This is not the only study to question whether neurogenesis occurs to a meaningful extent in the adult brain. One, led by pathologist Greg Sutherland of the University of Sydney, found a sharp drop-off in neurogenesis by age 4, for instance, with essentially none in adults. The difference “between 3 months of age and 3 years is marked,” he said. “My reading of this stark difference is that adult neurogenesis is a vestigial process,” producing very few new neurons.
He acknowledged, however, that the clash might come down to different scientists seeing a glass as half full or half empty: the “seemingly high figure of 700 new neurons a day [in one study] is, when compared to total neurons, similar to” the low numbers of new neurons he and his colleagues found. The many studies finding neurogenesis, he added, are “hard to counter.”